The menisci are fibrocartilaginous tissues situated between the femoral condyles and the tibial plateau. These structures are essential for normal biomechanical function of the knee, including load bearing, shock absorption, joint congruity, and joint stability. In addition to the pain and disability with the initial meniscal injury, damage or loss of meniscal tissue is associated with degenerative changes in the joint that ultimately lead to osteoarthritis (OA). Increased levels of the inflammatory cytokines, such as interleukin-1 (IL-1), have been measured in injured and degenerative joints. In addition, IL-1 has been shown to upregulate degradatiye enzymes, such as matrix metalloproteinases (MMPs), and also decrease matrix biosynthesis by meniscal cells. IL-1 has also been shown to significantly decrease repair strength, cell accumulation, and tissue formation at the interface in a meniscal repair model system. However, the mechanism(s) by which IL-1 inhibits repair of meniscal lesions is not yet known. The goals of this study are to identify the mechanism(s) by which IL-1 prevents the repair of meniscal lesions and to develop strategies to enhance the healing of meniscal tears in presence of IL-1. A novel in vitro model of integrative repair of the meniscus that consists of two concentric meniscus explants that naturally exhibit repair over several weeks of culture in vitro will be utilized for these studies. The effects of IL-1 on cell proliferation, cell migration, collagen and proteoglycan synthesis, MMP activity, and collagen and proteoglycan degradation will be determined. In the presence of IL-1, anabolic factors and inhibitors of MMPs will be used to identify and block the mechanisms of IL-1 activity that prevent integrative repair of the meniscus. The effects of different magnitudes of mechanical stress on the repair of a meniscal tear in the presence or absence of IL-1 will also be assessed. The broad, long-term objectives of this study are to identify downstream targets of IL-1 activity that could be targeted pharmacologically and/or mechanically and thus could ultimately be useful clinically to promote meniscal healing following injury and in patients with arthritis. This proposal is relevant to public health, as results will have implications with regard to both novel pharmacologic and physical therapy treatments for meniscus injury in patients with a joint injury or arthritis. Potential pharmacologic and mechanical treatments identified could ultimately be translated clinically to future treatments for meniscus repair. [unreadable] [unreadable] [unreadable]